Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with inheritable thrombophilia: the FRUIT‐RCT: a rebuttal

See also de Vries JIP, Hague WM and van Pampus MG; for the FRUIT‐Investigators. Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with inheritable thrombophilia: the FRUIT‐RCT: a reply to a rebuttal. This issue, pp 1196; de Vries JIP, van Pampus MG, Hague WM, Bezemer PD, Joosten JH, on behalf of FRUIT Investigators. Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset preeclampsia in women with inheritable thrombophilia: the FRUIT‐RCT. J Thromb Haemost 2012; 10 : 64–72.     

Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with inheritable thrombophilia: the FRUIT‐RCT

Summary. Background: Early‐onset hypertensive disorders (HD) of pregnancy and small‐for‐gestational age infants (SGA) are associated with placental vascular thrombosis, these often recur and are also associated with inheritable thrombophilia. Aspirin reduces the recurrence risk. Objectives: Adding low‐molecular‐weight heparin (LMWH) to aspirin at < 12 weeks gestation reduces the recurrence of HD in women with previous early‐onset HD (pre‐eclampsia, hemolysis, elevated liver enzymes and low platelets [HELLP] syndrome and eclampsia) and/or SGA, in the context of inheritable thrombophilia without antiphospholipid antibodies. Patients/methods: In a multicenter randomized control trial (RCT), 139 women included were < 12 weeks gestation. Inclusion criteria: previous delivery < 34 weeks gestation with HD and/or SGA; inheritable thrombophilia (protein C deficiency, protein S deficiency, activated protein C resistance, factor V Leiden heterozygosity and prothrombin gene G20210A mutation heterozygosity); and no antiphospholipid antibodies detected. Intervention: either daily LMWH (dalteparin, 5000 IU weight‐adjusted dosage) with aspirin 80 mg or aspirin 80 mg alone. Main outcome measures: Primary outcomes: recurrent HD onset (i) < 34 weeks gestation and (ii) irrespective of gestational age. Secondary outcomes: recurrent SGA, preterm birth, maternal/neonatal hospitalization, spontaneous abortion and individual HD. Analysis by intention‐to‐treat. Results: Low‐molecular‐weight heparin with aspirin reduced recurrent HD onset < 34 weeks gestation (risk difference [RD] 8.7%: confidence interval [CI] of RD 1.9–15.5%; P = 0.012; number needed to treat [NNT] 12). Recurrent HD irrespective of gestational age was not different between the arms. No women withdrew as a result of adverse effects. Trial Registration: http://www.isrctn.org ) (isrctn87325378). Conclusions: Adding LMWH to aspirin at < 12 weeks gestation reduces recurrent HD onset < 34 weeks gestation in women with inheritable thrombophilia and prior delivery for HD/SGA <34 weeks. However, close monitoring of the mother and fetus remains important throughout pregnancy.     

Molecular actions of heparin and their implications in preventing pre‐eclampsia

Summary

Pre‐eclampsia, a hypertensive disorder of pregnancy, continues to be a significant cause of global maternal morbidity. Low‐dose aspirin remains the only standard‐of‐care prophylactic therapy for preventing pre‐eclampsia, but is limited in efficacy. Heparin and its derivatives may further enhance the efficacy of aspirin therapy to prevent pre‐eclampsia, but the mechanisms mediating this augmentative effect are not known. Although heparin is an anticoagulant agent, it also possesses many anticoagulant‐independent properties that may be relevant in the prevention of pre‐eclampsia, including effects on placental, vascular and inflammatory function. This review summarizes the non‐anticoagulant properties of heparin, and extrapolates how these actions may influence the trajectory of pre‐eclampsia pathogenesis as a means of pathway‐specific therapy.

     

Low molecular weight heparin to achieve live birth following unexplained pregnancy loss: a systematic review

Summary. Background: The management of recurrent pregnancy loss is uncertain. Some cohort studies have identified an association between inherited thrombophilias and recurrent or late non‐recurrent pregnancy loss, which has prompted investigators to evaluate the benefit of low molecular weight heparin (LWMH) to achieve live birth. A similar benefit for LMWH has also been proposed independent of thrombophilia status. Objective and methods: We conducted a systematic review of randomized controlled trials to assess the benefit of LMWH in achieving live birth for women with a history of recurrent or late non‐recurrent pregnancy loss in the absence of antiphospholipid antibodies. Results: For the five studies that satisfied the eligibility criteria, the risk ratio of live birth for women with a history of pregnancy loss treated with LWMH compared with control ranged from 0.95 to 3.00. There was considerable heterogeneity among studies in terms of treatment effect (Q‐value was 41.7, P = 0.000, and I² = 90.4%) independent of thrombophilia status. There was also a wide variation among all studies in terms of definition of early or late pregnancy loss, thrombophilic risk factors, and number of prior pregnancy losses. Conclusion: There is a trend for increased live births when using LWMH for the prevention of recurrent pregnancy loss. Currently, there is insufficient evidence to support the routine use of LWMH to improve pregnancy outcomes in women with a history of pregnancy loss. Not only are additional studies necessary but standardized criteria for trials evaluating the benefit of an intervention in recurrent pregnancy loss should be established.     

Low‐molecular‐weight‐heparin and pregnancy,when the dose does it: a nephrologist’s opinion: reply to a rebuttal

See also Roeters van Lennep JE, Meijer E, Klumper FJ, Middeldorp JM, Bloemenkamp KW, Middeldorp S. Prophylaxis with low‐dose low‐molecular‐weight‐heparin during pregnancy and postpartum: is it effective? J Thromb Haemost 2011; 9 : 473–80; Stratta P, Canavese C, Cena T, Quaglia M, Pergolini P, Bellomo G, Magnani C. Low‐molecular‐weight‐heparin and pregnancy, when the dose does it: a nephrologist’s opinion: a rebuttal. This issue, pp 2127–9.     

Low‐molecular‐weight‐heparin and pregnancy,when the dose does it: a nephrologist’s opinion: a rebuttal

See also Roeters van Lennep JE, Meijer E, Klumper FJ, Middeldorp JM, Bloemenkamp KW, Middeldorp S. Prophylaxis with low‐dose low‐molecular‐weight‐heparin during pregnancy and postpartum: is it effective? J Thromb Haemost 2011; 9 : 473–80; Roeters van Lennep JE, Meijer E, Klumper FJCM, Middeldorp JM, Bloemenkamp KWM, Middeldorp S. Low‐molecular‐weight‐heparin and pregnancy, when the dose does it: a nephrologist’s opinion: reply to a rebuttal. This issue, pp 2129–30.     

Neuroprotective effects of ultra‐low‐molecular‐weight heparin in vitro and vivo models of ischemic injury

This study was conducted to demonstrate ultra‐low‐molecular‐weight heparin’s neuroprotective effects on ischemic injury both in vivo and in vitro studies. In vitro, the effect of ultra‐low‐molecular‐weight heparin was tested in cultured PC12 cells exposed to Earle’s solution containing sodium dithionite, to identify its neuroprotection to PC12 cells damaged by oxygen‐glucose deprivation (OGD). The cell injury was detected by the tetrazolium salt 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5 diphenyl‐2H tetrazolium bromide (MTT) assay. In vivo, male Wistar rats with middle cerebral artery occlusion were evaluated for infarct volume followed by the treatment with ultra‐low‐molecular‐weight heparin. The results in vitro showed that ultra‐low‐molecular‐weight heparin significantly inhibited PC12 cells damage induced by OGD. Results in vivo showed that vein injection of Ultra‐Low‐molecular‐weight heparin at doses of 0.5 and 1.0 mg/kg exerted significant neuroprotective effects on rats with focal cerebral ischemic injury by significantly reducing the infarct volume compared with the injury group. All the findings suggest that ultra‐low‐molecular‐weight heparin might act as a neuroprotective agent useful in the treatment of cerebral ischemia.     

Thrombophilia and its impact on pregnancy

In recent years thrombophilia has gained much attention as a risk factor for pregnancy complications. Whereas there is an established correlation between antiphospholipid-antibodies and pregnancy loss, data for other risk factors of thrombosis are less well established. Data suggest associations with antithrombin deficiency, hyperhomocysteinemia and also with factor V Leiden, prothrombin G20210A variation and protein S-deficiency. The association of thrombophilia with pre-eclampsia is still under discussion. A limited number of prospective studies did not reveal an increased risk for pregnancy complications in unselected women with thrombosis risk factors. In a single study low molecular weight heparin seemed to have a positive effect on pregnancy outcome after previous single or recurrent abortions. Experience in prevention of pre-eclampsia by administration of prophylactic heparin is very limited. Data on pregnancy complications in women with known heritable thrombophilia or a history of thrombosis are inconsistent as well. These women usually have a favourable pregnancy outcome. CONCLUSION: Thrombophilia screening might be justified in women with pregnancy loss. Treatment with low molecular weight heparin might be considered for those with pregnancy loss and thrombophilia. Further prospective studies and controlled interventional trials are urgently needed.     

Recurrent miscarriage and antiphospholipid antibodies: prognosis of subsequent pregnancy

Summary. Background: Although women with antiphospholipid antibodies (APLAs) are at increased risk of recurrent miscarriage, the outcome of a subsequent pregnancy is not clearly elucidated. Objectives: To assess the pregnancy outcome of a subsequent pregnancy in women with APLAs and compare this outcome with women with unexplained recurrent miscarriage. Methods: We performed a cohort study among all women who attended the Miscarriage Clinic at Liverpool Women’s Hospital between 1987 and 2006 after being referred due to recurrent miscarriage (≥ 2 consecutive pregnancy losses). All women underwent a standardized investigation sequence. Women with other reasons for recurrent miscarriage were excluded. Results: A total of 693 women fulfilled the selection criteria, of whom 176 (25%) had APLAs. One hundred and twenty‐two (69%) women with APLAs had a subsequent live birth compared with 324 (63%) women with unexplained recurrent miscarriage (OR 1.3, 95% CI 0.9–1.9). No differences were found for birth weight, gestational age, and intra‐uterine growth restriction. When treatment was analyzed, 53/67 (79%) of women with APLAs who had received aspirin and heparin during their pregnancy had a live birth, compared with 64/104 (62%) of women with APLAs who received aspirin only (adjusted OR 2.7, 95% CI 1.3–5.8). In unexplained recurrent miscarriage, stratification for treatment showed no differences in outcome. Conclusion: The prognosis of a subsequent pregnancy in women with APLAs is good. Although this was not a randomized clinical trial, combined treatment of aspirin and heparin seemed associated with a better outcome in women with APLAs, but not in women with unexplained recurrent miscarriage.     

Influence of thrombophilia in women with recurrent miscarriage: pros and cons

Recurrent miscarriage is a heterogeneous condition. A large number of studies have suggested a significant role for inherited and acquired thrombophilia in the development of abortion. Preliminary case-control studies and one prospective trial suggest that low molecular weight heparin is effective in preventing pregnancy loss in women with thrombophilia and previous recurrent miscarriage.     

Role of tissue factor in feto‐maternal development: a xiphos

Summary. In this review, the dual role of tissue factor (TF) in pregnancy is described. On the one hand, TF is required for embryonic and placental development in a successful pregnancy, and on the other hand, pathologic expression of TF can lead to serious pregnancy complications in humans and mice. Human studies show increased TF levels in plasma, amniotic fluid and and/or placentas of abnormal pregnancies affected by miscarriages, preterm birth, or pre‐eclampsia. Interestingly, using two mouse models, we found that blood‐borne TF plays a crucial role in the pathogenesis of pregnancy complications. TF on neutrophils and monocytes is a critical mediator in trophoblast injury and embryo damage in pregnancy loss induced by antiphospholipid antibodies and in the antibody‐independent CBA/J × DBA/2 model of miscarriages. Blockade of TF or genetic diminution prevented pregnancy complications, suggesting that TF may be a good target for therapy in patients with recurrent miscarriages, pregnancy loss, and pre‐eclampsia. In addition, statins, which downregulate TF, may constitute a good therapeutic option for women with pregnancy complications. Clinical trials should be conducted to confirm these observations in women.     

Thrombophilia and pregnancy complications: cause or association?

Summary.  Both acquired and inherited thrombophilia is associated with an increased risk of pregnancy failure (i.e. sporadic and recurrent miscarriage, late fetal loss), as well as hypertensive pregnancy complications such as pre-eclampsia and HELLP syndrome. The question of whether this relationship can be considered causal is rather philosophical. For practical purposes, the consistency and strengths of associations, potential mechanisms and, most importantly, the possibility to intervene with anticoagulants are reviewed. Relevant methodological issues in the case of thrombophilia and pregnancy complications consist of differences between observational and experimental research and quality issues in randomized controlled trials. The mechanisms associating thrombophilia and pregnancy complications are likely to involve effects on trophoblast differentiation rather than mere hypercoagulability. Therapeutic options comprise aspirin as well as (low molecular weight) heparin. For women with antiphospholipid antibody syndrome, this treatment is often suggested although the evidence is limited. For women with inherited thrombophilia and unexplained recurrent pregnancy loss, at present there is no evidence supporting treatment. Observational research is hampered by severe methodological flaws or inconsistent results. Two published randomized trials have not used an adequate comparator (i.e. no treatment or placebo). Currently, randomized controlled trials with no treatment or placebo are being carried out and results should be awaited before implementing a potentially harmful intervention in pregnant women with inherited thrombophilia and a history of pregnancy complications.     

Factor V Leiden is associated with pre‐eclampsia but not with fetal growth restriction: a genetic association study and meta‐analysis

Summary. Background: Adverse pregnancy outcomes have been related to environmental and/or genetic factors. Of interest are genes associated with the clotting system as any perturbation in the balance of thrombotic and thrombolytic cascades could affect the placental circulation and hence the viability of the developing fetus. Several previous reports using relatively small numbers of cases and controls have suggested that there is a relationship between poor pregnancy outcomes and two polymorphisms, one in the factor V gene, the 1691G to A change (rs6025) located on chromosome 1q23 (factor V Leiden, FVL), and the other in the prothrombin gene, 20210G to A change (rs1799963) on chromosome 11p11‐q12 (PT). These results, however, are conflicting. Methods: We genotyped 6755 mother/infant pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC) to determine whether maternal or fetal FVL or PT, either alone or in combination, are associated with fetal growth restriction (FGR) or pre‐eclampsia (PE). We also added the present results to previous cohort studies using meta‐analysis. Results: Smoking, primiparity and lower body mass index (BMI) were all associated with FGR, but neither maternal nor fetal FVL or PT, singly or in combination, were associated with FGR in the ALSPAC cohort. Meta‐analysis confirmed the lack of association between maternal FVL and FGR with a pooled odds ratio (OR) of 1.15 [95% confidence interval (CI) 0.95–1.39]. High BMI, primiparity, diabetes and chronic hypertension were all associated with pre‐eclampsia. Combining ALSPAC results with previous studies in a meta‐analysis indicated that maternal FVL is significantly associated with pre‐eclampsia, with a pooled OR of 1.49 (95% CI 1.13–1.96). Conclusion: Neither maternal nor fetal FVL or PT, singly or in combination, are associated with FGR; this contradicts previous case–control studies and meta‐analyses based on these studies. In a meta‐analysis of all published cohort studies to date, maternal FVL appears to increase the risk of pre‐eclampsia by almost 50%. This result is robust, homogeneous and does not appear to be affected by publication bias.     

Heparin‐induced non‐necrotizing skin lesions: rarely associated with heparin‐induced thrombocytopenia

See also Warkentin TE, Linkins L‐A. Non‐necrotizing heparin‐induced skin lesions and the 4T’s score. This issue, pp 1483–. Summary. Background: Recently, there has been an increasing number of reports regarding adverse skin reactions to subcutaneous heparin administration. Case series have implied that heparin‐induced skin lesions are predominantly associated with life‐threatening heparin‐induced thrombocytopenia (HIT) in at least 22% of patients. Skin lesions, therefore, have been included in clinical scores for HIT. Objectives: To determine the association of heparin‐induced skin lesions with HIT. This would have a pivotal impact on further anticoagulatory management in patients with heparin‐induced skin lesions. Patients/Methods: In our observational cohort study, 87 consecutive patients with heparin‐induced skin lesions (85 occurring during low‐molecular‐weight heparin administration) were evaluated using a standardized internal protocol, including HIT diagnostics (heparin‐platelet factor 4‐ELISA, heparin‐induced platelet activation assay), platelet count monitoring, clinical/sonographical screening for thrombosis, skin allergy testing and, if necessary, histology. Results: None of the observed heparin‐induced skin lesions was due to HIT; all lesions were caused by delayed‐type IV‐hypersensitivity reactions (DTH) instead. Even the cutaneous reaction in one patient with concomitant HIT could be classified histologically as DTH reaction, amounting to an association of heparin‐induced skin lesions and HIT in 1.2% (1/87; 95% confidence interval, 0.00–0.06). Conclusion: Heparin‐induced skin lesions associated with use of low‐molecular‐weight heparins do not seem to be strongly associated with a systemic immunologic reaction in terms of HIT and might rather be due to DTH reactions than due to microvascular thrombosis. Hence, we propose refining existing pretest probability scores for HIT, unless underlying causes have been clarified.     

Prophylaxis with low‐dose low molecular weight heparin during pregnancy and the puerperium: is it effective? Reply to a rebuttal

See also Roeters Van Lennep JE,Meijer E, Klumper FJCM, Middeldorp JM, Bloemenkamp KWM, Middeldorp S. Prophylaxis with low‐dose low molecular weight heparin during pregnancy and postpartum: is it effective? J Thromb Haemost 2011; 9: 473–80; Patel JP, Patel RK, Davies JG, Arya R. Prophylaxis with low‐dose low molecular weight heparin during pregnancy and the puerperium: is it effective? A rebuttal. This issue, pp 1269–71.     

Hereditary thrombophilia and fetal loss: a prospective follow‐up study

Summary. Background: As the placental vessels are dependent on the normal balance of procoagulant and anticoagulant mechanisms, inherited thrombophilia may be associated with fetal loss. Objectives: We performed a prospective study to investigate the relation between inherited thrombophilia and fetal loss, and the influence of thromboprophylaxis on pregnancy outcome. Patients and methods: Women were enrolled in the European Prospective Cohort on Thrombophilia (EPCOT). These included women with factor (F)V Leiden or a deficiency of antithrombin, protein C or protein S. Controls were partners or acquaintances of thrombophilic individuals. A total of 191 women (131 with thrombophilia, 60 controls) had a pregnancy outcome during prospective follow‐up. Risk of fetal loss and effect of thromboprophylaxis were estimated by frequency calculation and Cox regression modelling. Results: The risk of fetal loss appeared slightly increased in women with thrombophilia without a previous history of fetal loss who did not use any anticoagulants during pregnancy (7/39 vs. 7/51; relative risk 1.4; 95% confidence interval 0.4, 4.7). Per type of defect the relative risk varied only minimally from 1.4 for FV Leiden to 1.6 for antithrombin deficiency compared with control women. Prophylactic anticoagulant treatment during pregnancy in 83 women with thrombophilia differed greatly in type, dose and duration, precluding solid conclusions on the effect of thromboprophylaxis on fetal loss. No clear benefit of anticoagulant prophylaxis was apparent. Conclusions: Women with thrombophilia appear to have an increased risk of fetal loss, although the likelihood of a positive outcome is high in both women with thrombophilia and in controls.     

Anti‐PF4/heparin antibody formation postorthopedic surgery thromboprophylaxis: the role of non‐drug risk factors and evidence for a stoichiometry‐based model of immunization

Summary. Background: Heparin‐induced thrombocytopenia is an antibody‐mediated disorder exhibiting variable frequency in different clinical settings. Antibodies recognize PF4/heparin complexes formed at optimal stoichiometric molar ratios. Objective: To identify clinical factors influencing risk of anti‐PF4/heparin immunization. Patients/methods: We performed observational studies and exploratory analyses of the frequency of anti‐PF4/heparin antibody formation in 6324 patients who received enoxaparin or fondaparinux in four randomized controlled trials of postorthopedic surgery thromboprophylaxis. Variables included surgery type (knee vs. hip), timing of first anticoagulant dose (pre‐ vs. postsurgery), circumstances of surgery (elective vs. hip fracture), anticoagulant (enoxaparin vs. fondaparinux) and body‐mass index (BMI). We applied a stoichiometry‐based model that predicts immunization risk based on expected differences in PF4/anticoagulant ratios in different settings, and specifically used this model to predict the effect of increasing BMI quartiles upon relative risk (RR) of immunization for fondaparinux vs. enoxaparin. Results: Anti‐PF4/heparin immunization was more frequent after knee vs. hip surgery (particularly for enoxaparin), and when enoxaparin was given post‐ rather than pre‐elective surgery; however, the opposite occurred with hip fracture surgery, that is, antibody formation was more frequent when enoxaparin or fondaparinux was given presurgery. The RR of immunization for fondaparinux vs. enoxaparin decreased significantly for increasing BMI quartiles, an effect predominantly because of increasing immunization with enoxaparin at increasing BMI quartiles. Conclusions: Several non‐drug factors – including type and circumstances of surgery, timing of first anticoagulant dose and BMI – influence risk of anti‐PF4/heparin antibody formation, consistent with a stoichiometry‐based immunization model of PF4 and anticoagulant ratios occurring during the early peri‐operative period.     

Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a meta‐analysis of the literature

Summary. Venous thromboembolism (VTE) is one of the most relevant causes of maternal death in industrialized countries. Low molecular weight heparin (LMWH), continued throughout the entire pregnancy and puerperium, is currently the preferred treatment for patients with acute VTE occurring during pregnancy. However, information on the efficacy and safety of anticoagulant drugs in this setting is extremely limited. We carried out a systematic review and a meta‐analysis of the literature to provide an estimate of the risk of bleeding complications and VTE recurrence in patients with acute VTE during pregnancy treated with antithrombotic therapy. The weight mean incidence (WMI) of bleeding and thromboembolic events and the corresponding 95% confidence interval (CI) were calculated. Eighteen studies, giving a total of 981 pregnant patients with acute VTE, were included. LMWH was prescribed to 822 patients; the remainder were treated with unfractionated heparin. Anticoagulant therapy was associated with WMIs of major bleeding of 1.41% (95% CI 0.60–2.41%; I) antenatally and 1.90% (95% CI 0.80–3.60%) during the first 24 h after delivery. The estimated WMI of recurrent VTE during pregnancy was 1.97% (95% CI 0.88–3.49%; I² 39.5%). Anticoagulant therapy appears to be safe and effective for the treatment of pregnancy‐related VTE, but the optimal dosing regimens remain uncertain.     

彩色多普勒超声预测先兆子痫及小剂量阿司匹林防治的研究

目的：研究彩色多普勒超声预测先兆子痫的价值及小剂量阿司匹林防治的意义。方法：将47例子宫动脉血流参数及多普勒频谱异常中晚期妊娠妇女随机分成两组,治疗组（23例）给予小剂量阿司匹林（每天60mg,口服）治疗,对照组（24例）给予安慰剂,对比分析两组治疗结果。结果：治疗组有1例（4．3％）发生先兆子痫,对照组有5例（20．8％）发生先兆子痫,相关显著（P＜0．001）。治疗组无子痫发生（0％）,对照组1例（4．2％）发生产时子痫（P＞0．05）。治疗组平均妊娠期为38．25周,对照组为37．84周（P＞0．1）。治疗组胎儿出生体重平均为3169．37g,对照组为3085．49g（P＞0．05）。治疗组胎儿出生身长平均为48．64cm,对照组为47．88cm（P＞0．05）。结论：彩色多普勒超声对预测先兆子痫很有意义,对高危妊娠妇女给予小剂量阿司匹林治疗,可以减少先兆子痫和子痫的发病率。     

Increased levels of an apoptotic product in the sera from women with pre‐eclampsia

Pre‐eclampsia is associated with both maternal and foetal complications. Several studies have shown increased trophoblast apoptosis in the placenta of women with this condition. The aim of this study was to investigate whether increased apoptosis can be detected as elevated levels of an apoptotic product in serum samples from women with pre‐eclampsia. For this purpose, we used the M30‐Apoptosense® ELISA assay, which measures a neo‐epitope of cytokeratin 18 that is exposed after cleavage by caspases during apoptosis of epithelial cells (M30 antigen). The M30‐antigen concentrations were measured in the sera of 15 healthy pregnant women and 15 patients with pre‐eclampsia (gestation weeks 24–34). Patients with pre‐eclampsia had significantly higher serum M30‐antigen concentrations, median 120?U/L, compared to 15 healthy pregnant women matched for pregnancy length, median 104?U/L (p = 0.01). This is consistent with previous findings of increased trophoblast apoptosis in women with pre‐eclampsia and raises the possibility that M30‐antigen can be used as a serum marker for the severeness of this condition for the mother and child.